scholarly journals Preventive treatment with CGRP monoclonal antibodies restores brain stem habituation deficits and excitability to painful stimuli in migraine: results from a prospective case-control study

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Anne Thiele ◽  
Lara Klehr ◽  
Sebastian Strauß ◽  
Anselm Angermaier ◽  
Ulf Schminke ◽  
...  

Abstract Background & Objectives Calcitonin gene-related peptide ligand/receptor (CGRP) antibodies effectively reduce headache frequency in migraine. It is understood that they act peripherally, which raises the question whether treatment merely interferes with the last stage of headache generation or, alternatively, causes secondary adaptations in the central nervous system and might thus possess disease modifying potential. This study addresses this question by investigating the nociceptive blink reflex (nBR), which is closely tied to central disease activity, before and after treatment with CGRP antibodies. Methods We enrolled 22 patients suffering episodic migraine (21 female, 46.2 ± 13.8 years of age) and 22 age-/gender-matched controls. Patients received assessments of the nBR (R2 component, 10 trials, 6 stimuli/trial) before (V0) and three months (V3) after treatment with CGRP antibodies started, controls were assessed once. The R2 area (R2a) and habituation (R2h; gradient of R2a against stimulus order) of the stimulated/non-stimulated side (_s/_ns) following repeated supraorbital stimulation provide a direct readout of brainstem excitability and habituation as key mechanisms in migraine. Results All patients showed a substantial reduction of headache days/month (V0: 12.4±3.3, V3: 6.6 ± 4.9). R2a_s (Fglobal=5.86, p<0.001; block 1: R2a_s: -28%, p<0.001) and R2a_ns (Fglobal=8.22, p<0.001, block 1: R2a_ns: -22%, p=0.003) were significantly decreased, and R2h_ns was significantly enhanced (Fglobal=3.07, p<0.001; block 6: R2h_ns: r=-1.36, p=0.007) from V0 to V3. The global test for changes of R2h_s was non-significant (Fglobal=1.46, p=0.095). Changes of R2h significantly correlated with improvement of headache frequency (R2h_s, r=0.56, p=0.010; R2h_ns: r=0.45, p=0.045). None of the nBR parameters assessed at baseline predicted treatment response. Discussion We provide evidence that three months of treatment with CGRP antibodies restores brain stem responses to painful stimuli and thus might be considered disease modifying. The nociceptive blink reflex may provide a biomarker to monitor central disease activity. Future studies should evaluate the blink reflex as a clinical biomarker to predict treatment response at baseline and to establish the risk of relapse after treatment discontinuation. Trial registration This trial was prospectively registered at clinicaltrials.gov (ID: NCT04019496, date of registration: July 15, 2019).

2021 ◽  
Author(s):  
Anne Thiele ◽  
Lara Klehr ◽  
Sebastian Strauß ◽  
Anselm Angermaier ◽  
Ulf Schminke ◽  
...  

Abstract Background & ObjectivesCalcitonin gene-related peptide ligand/receptor (CGRP) antibodies effectively reduce headache frequency in migraineurs. It is understood that they act peripherally, which raises the question whether treatment merely interferes with the last stage of headache generation or, alternatively, causes secondary adaptations in the central nervous system and might thus possess disease modifying potential. This study addresses this question by investigating the nociceptive blink reflex (NBR), which is closely tied to central disease activity, before and after treatment with CGRP antibodies.MethodsWe enrolled 22 episodic migraineurs (21 female, 46.2 ± 13.8 years of age) and 22 age-/gender-matched controls. Patients received assessments of the NBR (R2 component, 10 trials, 6 stimuli/trial) before (V0) and three months (V3) after treatment with CGRP antibodies started, controls were assessed once. The R2 area (R2a) and habituation (R2h; gradient of R2a against stimulus order) of the stimulated/non-stimulated side (_s/_ns) following repeated supraorbital stimulation provide a direct readout of brainstem excitability and habituation as key mechanisms in migraine.ResultsAll patients showed a substantial reduction of headache days/month (V0: 12.4±3.3, V3: 6.6 ± 4.9). R2a_s (Fglobal=5.86, p<0.001; block 1: R2a_s: -28%, p<0.001) and R2a_ns (Fglobal=8.22, p<0.001, block 1: R2a_ns: -22%, p=0.003) were significantly decreased, and R2h_ns was significantly enhanced (Fglobal=3.07, p<0.001; block 6: R2h_ns: r=-1.36, p=0.007) from V0 to V3. The global test for changes of R2h_s was non-significant (Fglobal=1.46, p=0.095). Changes of R2h significantly correlated with improvement of headache frequency (R2h_s, r=0.56, p=0.010; R2h_ns: r=0.45, p=0.045). None of the NBR parameters assessed at baseline predicted treatment response.DiscussionWe provide evidence that three months of treatment with CGRP antibodies restores brain stem responses to painful stimuli and thus might be considered disease modifying. The nociceptive blink reflex may provide a biomarker to monitor central disease activity. Future studies should evaluate the blink reflex as a clinical biomarker to predict treatment response at baseline and to establish the risk of relapse after treatment discontinuation.Trial registrationThis trial was prospectively registered at clinicaltrials.gov (ID: NCT04019496, date of registration: July 15, 2019).


2017 ◽  
Vol 33 (S1) ◽  
pp. 67-67
Author(s):  
E Simpson ◽  
Matt Stevenson ◽  
Emma Hock ◽  
Ruth Wong ◽  
R Wakefield ◽  
...  

INTRODUCTION:Ultrasound (US) detects synovitis more accurately than clinical examination (CE) in people with rheumatoid arthritis (RA). This review aimed to investigate the use of US, compared to CE alone, in treatment strategies for RA, and to estimate its potential to be cost-effective in making treatment decisions.METHODS:A systematic review was conducted of studies: investigating RA treatment response or strategies that compared US with CE-assessed synovitis; and of tapering RA treatment (1). A model was constructed to investigate the potential cost-effectiveness of US in (i) selecting patients suitable for treatment tapering; and (ii) avoiding treatment escalation (2).RESULTS:Seven prospective cohort studies suggested US-detected synovitis was significantly associated with a treatment response or tapering failure, whereas in most cases clinical examination alone was not. Two randomized controlled trials (RCTs) identified suggested that US added to the Disease Activity Index (DAS)-based treatment strategies but did not significantly improve primary outcomes, but was associated with improved rate of DAS remission. The evidence showed that some patients (proportions varied widely) who had achieved low disease activity could have treatment tapered, with no, or little, short-term harm to the patient.The model estimated that an average reduction of 2.5 percent in the costs of biological disease-modifying anti-rheumatic drug (bDMARDs) was sufficient to cover the costs of performing US every three months. This value increased to 4 percent and 13 percent for the costs of conventional disease-modifying anti-rheumatic drug (cDMARDs) depending on the assumed regimen.CONCLUSIONS:Use of US to monitor synovitis could potentially be a cost-effective approach, given that low proportions of patients for whom clinicians consider amending treatment, would need to taper treatment, or remain on therapy without escalation. US could provide clinicians with more confidence in reducing the drug burden. However, there is considerable uncertainty in this conclusion due to lack of robust data relating to key parameters.


Author(s):  
Małgorzata Łączna ◽  
Damian Malinowski ◽  
Agnieszka Paradowska-Gorycka ◽  
Krzysztof Safranow ◽  
Violetta Dziedziejko ◽  
...  

Abstract Aim Leflunomide is a disease-modifying antirheumatic drug used in therapy for rheumatoid arthritis (RA). Previous studies indicated that oestrogens and androgens may affect the response to leflunomide in RA patients. The synthesis of androgens is regulated by cytochrome CYB5A. The aim of this study was to examine the association between the CYB5A gene rs1790834 polymorphism and the response to leflunomide in women with RA. Methods The study included 111 women diagnosed with RA. Leflunomide was administered in monotherapy at a dose of 20 mg/day. All patients underwent a monthly evaluation for 12 months after the initiation of treatment with leflunomide. Results After 12 months of therapy, the changes in individual disease activity parameters, such as: DAS28, ESR, CRP and VAS, were not statistically significantly different between rs1790834 genotypes in the Kruskal–Wallis test. Conclusions The results of our study suggest lack of statistically significant association between the CYB5A gene rs1790834 polymorphism and the response to leflunomide in women with RA.


2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 97.1-98
Author(s):  
S. Shoop-Worrall ◽  
K. Hyrich ◽  
L. Wedderburn ◽  
W. Thomson ◽  
N. Geifman

Background:In children and young people (CYP) with JIA, we have previously identified clusters with different patterns of disease impact following methotrexate (MTX) initiation. It is unclear whether clusters of treatment response following etanercept (ETN) therapy exist and whether, in a group of CYP who have responded inadequately to or had adverse events on methotrexate, similar treatment response patterns exist. Novel response patterns would aid stratified treatment approaches through better understanding and potential forecasting of more specific response patterns across multiple domains of disease.Objectives:To identify and characterise trajectories of juvenile arthritis disease activity score (JADAS) components following ETN initiation for JIA.Methods:ETN-naïve CYP with non-systemic JIA were selected if enrolled prior to January 2019 in at least one of four CLUSTER consortium studies: BSPAR-ETN, BCRD, CAPS and CHARMS, at point of starting ETN as their first biological therapy. JADAS components (active joint count, physician’s global assessment (0-10cm), parental global evaluation (0-10cm) and standardised ESR (0-10) were collected at ETN initiation and during the following year.Multivariate group-based trajectory models, that identify clusters of CYP with similar patterns of change over time, were used to explore ETN response clusters across the different JADAS components. Censored-normal (global scores, ESR) and zero-inflated Poisson (active joint count) models were used, adjusting for year of ETN initiation. Optimal models were selected based on a combination of model fit (BIC), parsimony, and clinical plausibility.Results:Of the 1003 CYP included, the majority were female (70%) and of white ethnicity (90%), with rheumatoid factor-negative JIA the most common disease category (39%).The optimal model identified five trajectory clusters of disease activity following initiation of ETN (Figure 1). Clusters following ETN were similar and covered similar proportions of CYP to those previously identified following MTX: Fast (Group 1: 13%) and Slow (Group 2: 10%) response, active joint count improves but either physician (Group 3: 6%) or parent global scores (Group 4: 34%) remain persistently raised and a group with persistent raised scores across all JADAS components (Group 5: 36%). Compared to the persistent disease cluster, those with greater improvement had lower age and higher functional ability at ETN initiation and those with persistent raised parent global scores had lower ESR levels and were less likely to be RF-positive at ETN initiation.Figure 1.Clusters identified following ETN initiation in children and young people recruited to the UK BSPAR-ETN, BCRD, CAPS and CHARMS studies.Conclusion:This study has identified that within CYP initiating ETN, similar response clusters are evident to those previously identified following MTX. This commonality suggests a new framework for understanding treatment response, beyond a simple responder/non-responder analysis at a set point, which applies across multiple drugs despite different mechanisms of action and previous unfavourable treatment outcomes. Understanding both clinical factors associated with, and biological mechanisms underpinning, these clusters would aid stratified medicine in JIA.Acknowledgements:We thank the children, young people and families involved in CLUSTER, as well as clinical staff, administrators and data management teams. Funding for CLUSTER has been provided by generous grants from the MRC, Versus Arthritis, GOSH children’s charity, Olivia’s vision and the NIHR Manchester and GOSH BRC schemes.Disclosure of Interests:Stephanie Shoop-Worrall: None declared, Kimme Hyrich Speakers bureau: Abbvie, Grant/research support from: BMS, UCB, Pfizer, Lucy Wedderburn Speakers bureau: Pfizer, Grant/research support from: Abbvie, Sobi, Wendy Thomson Grant/research support from: Abbvie, Sobi, Nophar Geifman Grant/research support from: Abbvie, Sobi


2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1437.1-1438
Author(s):  
A. Fazaa ◽  
H. Boussaa ◽  
S. Miladi ◽  
K. Ouenniche ◽  
L. Souabni ◽  
...  

Background:In the recent decades, biological disease-modifying antirheumatic drugs (bDMARDs) have significantly improved management and quality of life in patients with rheumatoid arthritis (RA) and spondyloarthritis (SpA).However, bDMARDs have also a strong influence on the immune system, leading to a risk of serious infection. Reactivation of hepatitis B (HBV) and C (HCV) virus is one of the most redoubtable complications of these immunosuppressive agents.Objectives:The aims of this study were to determine the screening rate for hepatitis B and C before starting a biological treatment and to examine the prevalence of their markers in patients with RA or SpA.Methods:Our study evaluated all patients included in the Tunisian registry BINAR (Biologic National Registry) since 2018 who had RA (ACR/EULAR 2010) or SpA (ASAS criteria) aged with more than eighteen years old and receiving their first bDMARDs during the two past years.The following information were retrieved from the registry: demographic data on the patients, disease parameters, medication, HBV surface antigen (HBs Ag), antibody to HBs Ag (Anti HBs), antibody to HBV core antigen (Anti HBc), HBV-DNA, antibody to HCV (anti HCV) status and liver function tests (AST: aspartate aminotransferase; ALT:alanine aminotransferase).Results:A total of 298 patients was included, 111 men and 178 women, with a mean age of 49.2 ± 14.1 years old [18-79]. Among them, 58.7% were diagnosed with RA and 41.3% were diagnosed with SpA. The mean disease duration was 6.7±3.5 years [1-12] in patients with RA and 6.5±3 [1-12] in patients with SpA. The mean Disease Activity Score (DAS28) and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) were respectively of 4.9±1.5 [1-8] and 4.1±1.8 [0-9].Therapeutically, 167 patients (56%) were on Prednisone at a mean daily posology of 8.2±5.4 mg [4-60] and 70.3% on conventional synthetic disease modifying antirheumatic drug (csDMARD) in association with bDMARDs. It was about Tumor Necrosis Factor alpha antibodies (anti TNF a) in 87.9% of cases, Tocilizumab in 10.4% of cases and Rituximab in 5% of cases.A screening of HBV was performed in 286 patients (96%). Ag HBs was positive in two cases (0.7%), and anti-HBc was positive in 16 cases (6.4%) which indicate a prior HBV infection. Fifteen patients (6%) were immunized with positive anti HBs. HBV-DNA was measured in 177 cases (66.8%) and was positive in 15 patients (6%).HCV infection was searched in 282 patients (94.6%) and anti-HCV was negative in all cases.AST and ALT mean rates were respectively of 18.3 [2-108] and 17.9 UI/l [2-74]. A perturbation of these liver function tests was observed in 13 patients (4.4%).Conclusion:Screening for hepatitis B and C were performed respectively in 96% and 94% of our Tunisian patients before receiving any bDMARDs. This should be systematic to avoid HBV reactivation which can lead to fulminant hepatic failure with a severe prognosis.Disclosure of Interests:None declared


2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 422-423
Author(s):  
Y. Erez ◽  
A. Karakas ◽  
S. B. Kocaer ◽  
T. Yüce İnel ◽  
S. Gulle ◽  
...  

Background:The frequency of comorbidities has increased in spondyloarthritis patients compared to the general population. The effect of comorbidities on tumour necrosis factor alpha inhibitor (TNFi) drug retention and treatment response has not been well evaluated.Objectives:The purpose of this study to assess the impact of comorbidities on the first TNFi drug survival and treatment response in patients with axial spondyloarthritis (axSpA) registered in theTURKBIOdatabase.Methods:In this study, the frequency of comorbidities, disease activity scores at baseline and month 6 and drug retention were recorded in AxSpA patients iniating first TNFi treatment between 2011 and 2019. Kaplan Meier plot and log rank tests were used for drug survival analysis. Cox regression analysis with HR was performed to evaluate the correlation between comorbidities and drug survival.Results:There were 2428 patients with AxSpA (39.3% female) who used their first TNFi during the study period. Among them, a total of 770 (31%) had at least one comorbid disease. Hypertension was the most common comorbidity (9.7%), followed by the affective disorders (8%) and chronic lung disease (5.8%). The baseline characteristics of patients are shown in Table 1.The presence of any comorbidity did not impact the first TNFi retention (Figure 1). When comorbidities were analysed seperately, we found that only history of cerebrovascular event was negatively associated with drug retention rate (HR: 6.9, p:0.008). There was no statistically significant difference in Bath AS Disease Activity Index 50% (BASDAI50) response between patients with and without comorbidity at 6 months. Less axSpA patients with comorbidity achieved a ASDAS score ≤ 2.1 compared to patients without comorbidity at 6 months.Table 1.Baseline Characteristics of PatientsRadiographic Spondyloarthritis, n (%)2318 (95.5)Female, n(%)954 (39.3)Age, year42.2±11.8Age at diagnosis, years32.5± 11.3Age at initial TNFi, years39.4 ± 11.1Symptom duration, years9.7± 7.5Time to initial TNFi, years7±6.8HLA-B27- positivity, n (%)1144 (47.1)Smokers, n (%)1068 (44)Baseline BASDAI35.5±22.2Baseline ASDAS-CRP2.8±1.1Baseline CRP (mg/L)15.7±24.4VAS global patient46.6±28.7-Quantitative variables are presented as mean ± SD, and qualitative variables are presented as frequency and percentage-ASDAS-CRP, Ankylosing Spondylitis Disease Activity Score using C-reactive protein VAS, visual analogue scaleConclusion:The results of this study demonstrated that the presence of previous cerebrovascular event decreased the first TNFi survival in patients with axSpA. It also suggested that comorbidities might decrease TNFi treatment response.Disclosure of Interests:None declared


2021 ◽  
Vol 14 ◽  
pp. 175628642110064
Author(s):  
Yinan Zhang ◽  
Amber Salter ◽  
Shan Jin ◽  
William J. Culpepper ◽  
Gary R. Cutter ◽  
...  

Background: Disease-modifying therapies (DMTs) for multiple sclerosis (MS) are approved for their ability to reduce disease activity, namely clinical relapses and signal changes on magnetic resonance imaging (MRI). Disease activity appears age dependent. Thus, the greatest benefit would be expected in younger people with MS (PwMS) whereas benefits in the elderly are uncertain. Methods: Real-world data were obtained from PwMS from the North American Research Committee on Multiple Sclerosis (NARCOMS) registry and the US Department of Veterans Affairs Multiple Sclerosis Surveillance Registry (MSSR). Results: 6948 PwMS were surveyed from NARCOMS, and the MSSR had 1719 participants. In younger adult PwMS 40-years old or less, 183 (61.4%) in NARCOMS and 179 (70.5%) in the MSSR were prescribed DMTs. Among PwMS over age 60, 1575 (40.1%) in NARCOMS and 239 (36.3%) in the MSSR were prescribed DMTs. More PwMS in the age group of 31–40 ( p = 0.035) and 41–50 ( p = 0.001) in the MSSR were using DMTs compared with PwMS of the same age groups in NARCOMS. Conclusion: These findings suggest that DMTs are under-utilized in the younger population and continue to be commonly prescribed in the elderly. Broader access may explain the higher prescription rate of DMTs in US veterans.


2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Lucie Nekvindová ◽  
Jiří Vencovský ◽  
Karel Pavelka ◽  
Pavel Horák ◽  
Zlatuše Křístková ◽  
...  

Abstract Background Treat-to-target (T2T) is a widely accepted strategy for patients with rheumatoid arthritis (RA). It recommends attaining a goal of at least low disease activity (LDA) within 6 months; otherwise, the current therapy should be modified. We aimed to investigate whether switching a first-line targeted therapy (TT) in patients not reaching LDA within 6 months leads to a higher probability of meeting LDA at the 12-month visit in daily clinical practice using data from Czech registry ATTRA. Methods We included patients with RA starting the first-line TT from 1 January 2012 to 31 January 2017 with at least 1-year follow-up. We created four mutually exclusive cohorts based on (1) switching to another TT within the first year and (2) reaching a treatment target (DAS28-ESR ≤ 3.2) at the 6-month visit. The primary outcome was the comparison of odds for reaching remission (REM) or LDA at the 12-month visit between patients switching and not switching TT after not reaching treatment target at 6 months. Before using logistic regression to estimate the odds ratio, we employed the propensity score to match patients at the 6-month visit. Results A total of 1275 patients were eligible for the analysis. Sixty-two patients switched within the first 5 months of the treatment before evaluating treatment response at the 6-month visit (C1); 598 patients reached the treatment target within 6 months of therapy (C2); 124 patients did not reach treatment response at 6-month visit and switched to another therapy (C3), and 491 patients continued with the same treatment despite not reaching LDA at the 6-month visit (C4). We matched 75 patients from cohort C3 and 75 patients from C4 using the propensity score. Patients following the T2T principle (C3) showed 2.8 (95% CI 1.4–5.8; p = 0.005) times increased likelihood of achieving REM/LDA at the 12-month visit compared to patients not following the T2T strategy (C4). Conclusions In daily clinical practice, the application of the T2T strategy is underused. Switching TT after not reaching REM/LDA within the first 6 months leads to a higher probability of achieving REM/LDA in RA patients at the 12-month visit.


2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 929.1-930
Author(s):  
Y. M. Pers ◽  
V. Valsecchi ◽  
T. Mura ◽  
S. Aouinti ◽  
N. Filippi ◽  
...  

Background:Telemedicine has found wider application in chronic diseases for encouraging tight home-monitoring in order to improve patients’ outcome (Smolen et al. 2017).In previous studies, a high feasibility and high patient-satisfaction rate was found as well as the evidence for a superior or equal effectiveness of telemedicine compared to the standard face-to-face approach, however the results were weakened by some methodological biases and wide heterogeneity of interventions, thus preventing to draw definitive conclusions (Piga et al. 2017; Najm, Gossec, et al. 2019).Objectives:In rheumatoid arthritis (RA), telemedicine may allow a tight control of disease activity while reducing hospital visits. We developed a smartphone application connected with a physician’s interface to monitor RA patients. We aimed to assess the performance of this e-Health solution in comparison with routine practice in the management of patients with RA.Methods:A 6-month pragmatic, randomized, controlled, prospective, clinical trial was conducted in RA patients with high to moderate disease activity starting a new Disease Modifying Anti-Rheumatic Drug (DMARD) therapy. Two groups were established: “connected monitoring” and “conventional monitoring”. The primary outcome was the number of physical visits between baseline and 6 months. Secondary outcomes included adherence, satisfaction, changes in clinical, functional, and health status scores (SF-12).Results:Of the 94 randomized patients, 89 completed study: 44 in the “conventional monitoring” arm and 45 in the “connected monitoring” arm. The total number of physical visits between baseline and 6 month was significantly lower in the “connected monitoring” group (0.42 ± 0.58 versus 1.93 ± 0.55; p<0.05). No differences between groups were observed in the clinical and functional scores. A better quality of life for SF-12 subscores (Role-Physical, Social-Functioning and Role-Emotional) were found in the “connected monitoring” group.Conclusion:According to our results, a connected monitoring reduces the number of physical visits while maintaining a tight control of disease activity and improving quality of life in patients with RA starting a new treatment.References:[1] Najm, Aurelie, Laure Gossec, Catherine Weill, David Benoist, Francis Berenbaum, and Elena Nikiphorou. 2019. “Mobile Health Apps for Self-Management of Rheumatic and Musculoskeletal Diseases: Systematic Literature Review.”JMIR MHealth and UHealth7 (11): e14730.https://doi.org/10.2196/14730.[2] Piga, Matteo, Ignazio Cangemi, Alessandro Mathieu, and Alberto Cauli. 2017. “Telemedicine for Patients with Rheumatic Diseases: Systematic Review and Proposal for Research Agenda.”Seminars in Arthritis and Rheumatism47 (1): 121–28.https://doi.org/10.1016/j.semarthrit.2017.03.014.[3] Smolen, Josef S, Robert Landewe, Johannes Bijlsma, Gerd Burmester, Katerina Chatzidionysiou, Maxime Dougados, Jackie Nam, et al. 2017. “EULAR Recommendations for the Management of Rheumatoid Arthritis with Synthetic and Biological Disease-Modifying Antirheumatic Drugs: 2016 Update.”Annals of the Rheumatic Diseases76 (6): 960–77.https://doi.org/10.1136/annrheumdis-2016-210715.Disclosure of Interests:None declared


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